2686 7,
are considered. This observation indicates that tryptophan interacts so strongly with the enzyme that the rotational motions of the amino acid are essentially identical with those of the enzyme and provides support for the proposition that chymotrypsin binds substrates tightly enough to seriously curtail molecular motion in the sub~trate.~’It remains for further experimentation to more precisely define the details of this interaction. Acknowledgments. We are indebted to Professors B. R. Baker and D. V. S a d for helpful discussions. This work was supported by Grant GM-14692 from the National Institutes of Health.
4qaa 3kT
=-
A recent crystallographic study of chymotrypsin at 2-8, resolution shows that the over-all dimensions of the molecule are approximately 45 X 35 X 38 If the mean of these dimensions (39 A) is taken as the effective radius of the enzyme in solution, the rotational correlation time for the enzyme as a whole is estimated to be 4 X 10-8 sec. The agreement between the calculated rotational correlation time of the enzyme molecule as a whole and the correlation time of tryptophan in the tryptophan-enzyme complex as determined by nmr is striking when the approximations involved (26) B. W. Matthews, P. B. Sigler, R. Henderson, and D. M. Blow,
(27) M. L.Bender, F. J. Kezdy, and C. R. Gunter, J . A m . Chem. Soc., 86, 3714 (1964).
Nature, 214, 652 (1967).
Communications to the Editor The Borohydride-Catalyzed Reaction of Diborane with Epoxides. The Anti-Markovnikov Opening of Trisubstituted Epoxides Sir: Diborane is an interesting reducing agent with unusual characteristics. However, in contrast to the simplicity of most other reactions, the reaction of diborane with epoxides is quite complex.2 Thus, the
. 1.0 3
‘g 0.9 0
i,x 0.8 I
3
9 0.7 N” c
Icl
-o 0.6 3
2 0.5 L
c
- 0.4 vi
0
E 0.3 3
0.2
.-3
20.1 z
0
1 2 3 4 Reaction time, hr.
5
reaction of 1,2-butylene oxide with diborane in tetrahydrofuran at 25” is a relatively slow reaction, requiring approximately 48 hr to proceed to the utilization of one “hydride” per mole of epoxide. However, analysis of the reaction mixture reveals the presence of only 48 % of butanol (4 % 1- and 96 % 2-). The reaction is even more complex with trisubstituted epoxides, such as 1-methylcyclohexene oxide. In such cases the reaction proceeds with the utilization of 2 moles of hydride per mole of epoxide, with 1 mole of hydrogen being evolved. Only trace amounts of the simple alcohols are found in the reaction mixture. The major product is evidently an organoborane which is oxidized with alkaline hydrogen peroxide to the isomeric 2-hydroxymethylcyclohexanols. The presence of even minor amounts of sodium or lithium borohydride has a major effect on both the speed of the reaction and its course. In Figure 1 are shown the curves for the reaction of 1,2-butylene oxide with diborane in the presence and absence of a small quantity of sodium borohydride. Not only is the rate affected, but the yield in 1 hr rises to 95 % 2-butanol. In the case of trisubstituted epoxides, such as l-methylcyclohexene oxide, the rate of the reaction is also increased. Moreover, the course of the reaction is modified tremendously. One mole of hydride per mole of compound is utilized, hydrogen is not evolved, and there is observed a predominant anti-Markovnikov opening of the epoxide ring (1).
6
Figure 1. The reaction of borane (0.33 M ) with 1,2-butylene oxide (0.25 M ) in the presence (A) and absence (0) of sodium borohydride (0.036 M ) .
(1) H . C . Brown, “Hydroboration,” W. A . Benjamin, Inc.,New York, N. Y . ,1962. (2) D. J. Pasto, C. C. Cumbo, and J. Hickman, J . Am. Chem. Soc., 88,2201 (1966).
Journal of the American Chemical Society
1 90:lO / May 8, 1968
NaBH, catalyrrt
(1)
26%
14%
(3) The solubility of sodium ;orohydride in 0.33 M THF-BHs was determined to be 0.036 M at 25 .
2687 Table I. The Borohydride-Catalyzed Reduction of Representative Epoxides Epoxide0
Reagent
1,2-Butylene oxide
Temp, "C
Time,' hr
Yield,
BH3*
25
48
48
BH3(NaBH4)c AlH3 .2AIClad BHab BH3(NaBH4)c
25 0 0 0
1.0 1.0 24 48
95 71 4
BM3(LiBH4)"
0
24
98
1-Methylcyclopentene oxide
BH3b BH3(LiBH4)e
25 0
48 24
2h 88
1-Methylcyclohexene oxide
BHsb BH3(NaBH4)c
25 0
24 24
Trh 100
2-Methyl-2-butene oxide
1-Methylcycloheptene oxide a-3,4-Epoxycarene
Products0
1-Butanol (4) 2-Butanol (96) 2-Butanol (lob) 2-Butanol (100) 3-Methyl-2-butanol (100) 3-Methyl-2-butanol (78) 2-Methyl-2-butanol (22) 3-Methyl-2-butanol (75) 2-Methyl-2-butanol (25) 2-Methylcyclopen tanols cis-2-Methylcyclopentanol(72) 1-Methylcyclopentanol (28)
59
BH3(LiBH4)e
0
3.0
100
AIH3. 2AIChd
0
1.0
40'
BH3b BH3(LiBH4)e
25 0
6.0 24
Trh 41
BH3(LiBH4)e
0
96
70
(z)
cis-2-Methylcyclohexanol (74) 1-Methylcyclohexanol (26) cis-2-Methylcyclohexanol (74) 1-Methylcyclohexanol(26) cis-2-Methylcyclohexanol(47) trans-2-Methylcyclohexanol(29) 1-Methylcyclohexanol (24) cis-2-Methylcycloheptanol (83) 1-MethylcycloheptanoI(l7) Neocaranol (66) Caranol (1) 3-Caranol (33)
a 0.25 M in THF. * 10 mmoles of BH8 for 10 mmoles of epoxide. e 13.3 mmoles of BH3 and 0.1 g of NaBH4 for 10 mmoles of epoxide. 10 mmoles of BH3 and 10 mmoles of LiBHl for 10 mmoles of 10 mmoles of AIH3 and 20 mmoles of AlC13 for 10 mmoles of epoxide. epoxide. Reactions were followed and halted after the hydride uptake became essentially constant. 0 Only the simple reduction products are indicated. Analysis by glpc. Hydrogen evolved during reaction. After oxidation with alkaline hydrogen peroxide, 70-80x yields of diols (2-hydroxymethylcycloalkanols)could be isolated. i The remaining 6Oz was I-methylcyclopentylcarbinol(see eq 4).
'
A somewhat faster reaction, with similar products, could be realized by the use of higher concentrations of the more soluble lithium borohydride.
6
H,C
~
H3S:
The reaction presumably involves preferentially the attack by borohydride at the polarized tertiary position, with inversion, to form the cis-2-methylcycloalkanol,~ whereas electrophilic attack by diborane occurs at the methyl group (2). Mixed hydride (LiAlH4: AICI, 1 : 4) has also been reported to give the less substituted carbinol as a major product.6 However, the low yields suggest that the tertiary alcohol is probably formed preferentially but is selectively destroyed (3). In the case of I-methylcyclohexene oxide, mixed hydride gave a complex mixture of products (4).
OBHC
:6BH3
H,BCH,
(2)
,OBH,
+ H,
BH,
(CH,)zCCH&H3
I
BHALiBH,)
7
CH3-k-CH-CH, \/
0
L LiAlH,.4AICIt
OH 25%
(CHJZCHCHCH3
I
OH 75%
(3)
0%
32%
(4) 10046
The generality of this anti-Markovnikov opening of trisubstituted epoxides is indicated by the results with 2-methy1-2-buty1ene Oxide' l-methylcyclopentene Oxide' -methylcycloheptene Oxide, and a-3,4-epoxycarene (Table I). It is noteworthy that this procedure provides a simple entry into the neocaranol series, otherwise very difficult to achieve.
19%
11%
60%
Consequently, the present procedure appears to offer (4) H. C. Brown and A. Suzuki, J. Am. Chem. Soc., 89, 1933 (1967). ( 5 ) An alkoxy borohydride would be the first product, but it is known that such derivatives are rapidly converted to borohydride by diborane, accounting for the need of only minor amounts of borohydride: H . I . Schlesinger. H. c. Brown, H . R . Hockstra, and L. R. Rapp, ibid., 75, 199 (1953). (6) E.L. E M , Record Chem. Progr., 22, 129 (1961).
Communications to the Editor
2688
major advantages for the anti-Markovnikov opening of such trisubstituted epoxides. The following procedure is representative. A dry 100-ml flask, fitted with a rubber syringe cap and a magnetic stirring bar, was placed in an ice bath and flushed with dry nitrogen and then maintained under a static atmosphere of the gas. There was then introduced into the flask 10 mmoles of borane (4.4 ml of a 2.28 M solution in THF), 10 mmoles of lithium borohydride (5.6 ml of a 1.79 M solution in THF), and 20 ml of THF. The reaction was initiated by the injection of 10 mmoles of I-methylcyclopentene oxide (0.981 gj in 10 ml of T H F at 0". After 24 hr at 0", the reaction mixture was hydrolyzed with 10 ml of a 1 :1 mixture of 1.0 M sulfuric acid and T H F ; 10 mmoles of cyclohexanol (10 ml of a 1.00 M solution in THF) was added as an internal standard. Potassium carbonate was added to saturate the aqueous phase, and the T H F phase was separated, dried over anhydrous magnesium sulfate, and analyzed by glpc. The analysis revealed an 88.3% yield of alcohols (27.6 % l-methylcyclopentanol and 72.4 % cis-2methylcyclopentanol). No trace of the trans isomer was detected. The hydroboration-oxidation of I-substituted cycloalkenes provides a highly satisfactory route to the pure trans-2-substituted cycloalkanols. The present development now provides a convenient route to the isomeric cis derivatives.
meta chlorides 1421 and 11-Cl, respectively. On hydrolysis of the mixture in 7 0 z aqueous acetone in the presence of 1 equiv of N a H C 0 3 for 3 hr at 7 5 O , I-Cl was converted into the homo-para exo-alcohol I-OH, mp 5 1-52 O,j whereas 11-CI remained unreacted ; I-OH and 11-C1 were separated by chromatography. When the reaction with the separated 11-C1 was carried out once again for 6 hr, 11-Cl was isolated in a pure state, n Z 2 1.5670. ~ Treatment of I-OH with thionyl chloride led to I-C1, bp 115' (1 mm), n Z 5 ~
CH30&x
11-c1,x = c1 11-OH,X = OH
x
I-CI, = c1 I-OH, X OH E
x V-OH, X = OH V-OBs, X = OBs
(7) Graduate assistant on Research Grant DA 31-124 ARO(D) 453, supported by the U.S . Army Research Office, Durham.
Herbert C. Brown, Nung Min Yoon? Richard B. Werherill Laboratory Purdue Unicersiry, Lafayerte, Indiana 47907 Receiwd March I , I968
VI-OH, X = OH VI-OBs, X = OBs
Solvolyses of 6- and 7-Methoxybenzonorbornen-2-yl Derivatives. Directing Effects of a Methoxy Substituent for Participation Sir: Studies of substituent effects such as carried out by us in the solvolysis of benzonorbornenyl brosylates have been evaluated as a decisive test for n-participation effects.2 We now report the directing effects of a methoxy substituent in the solvolyses of 6- and 7methoxybenzonorbornen-2-yl derivatives I and 11, evidencing the presence of large participation in solvolysis of these compounds. The hydrochlorination of benzonorbornadiene was reported to give solely exo-2-chlorobenzonorbornadiene. The reaction with 6-methoxybenzonorbornadiene4 gave a 7 : 3 mixture of homo-para and homo(1) (a) H. Tanida,J. A m . Chem. SOC.,85, 1703 (1963); (b) H.Tanida, T. Tsuji, and H. Ishitobi, ibid., 86, 4904 (1964); (c) H.Tanida and H. Ishitobi, ibid., 88, 3663 (1966); (d) H.Tanida, Y. Hata, S. Ikegami, and H. Ishitobi, ibid., 89,2928 (1967). (2) (a) P. D. Bartlett, "Nonclassical Ions," W. A. Benjamin, Inc., New York, N. Y.,1965; (b) N. Brookhart, A. Diaz, and S. Winstein, J . A m . Chem. Soc., 88, 3135 (1966), ref 12; (c) H . C. Brown and I
